Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma;however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. The importance of common inherited variants in the relevant pathways and their interactions with UV exposure history in causing melanoma is largely unknown. We propose to evaluate several new hypotheses and also to extend our previous work to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in US Caucasians. Many of them have not been evaluated previously with melanoma risk. No previous studies examined the interactions of these genes with UV exposure history. Using a nested case-control design, we will include 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts, the Nurses Health Study, Nurses Health Study II, and the Health Professional Follow-up Study. We will systematically survey common genetic variation at each locus using two complementary approaches;1) evaluating SNPs with potential functional relevance and 2) choosing tag-SNPs to test for associations of unknown common functional variants with melanoma risk. We will also perform exploratory pathway analyses, potentially incorporating information on the biological function of the genes and polymorphisms. In addition, we will assess the interactions between these genetic variants and intermittent UV exposure history, i.e. sun exposure while wearing a bathing suit and indoor tanning device usage, on melanoma risk. This innovative work will move this field forward, by systematically evaluating these common variants using these complementary approaches. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohorts, including cohort characteristics, quality of design, high follow-up rate, large sample size, prospective host factor assessment, and high response rate of retrospective questionnaires. Our proposal will also take advantage of the previously identified and confirmed cases of melanoma as well as stored bio-specimens. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma;however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. We propose to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma;however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. The importance of common inherited variants in the relevant pathways and their interactions with UV exposure history in causing melanoma is largely unknown. We propose to evaluate several new hypotheses and also to extend our previous work to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in US Caucasians. Many of them have not been evaluated previously with melanoma risk. No previous studies examined the interactions of these genes with UV exposure history. Using a nested case-control design, we will include 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts, the Nurses Health Study, Nurses Health Study II, and the Health Professional Follow-up Study. We will systematically survey common genetic variation at each locus using two complementary approaches;1) evaluating SNPs with potential functional relevance and 2) choosing tag-SNPs to test for associations of unknown common functional variants with melanoma risk. We will also perform exploratory pathway analyses, potentially incorporating information on the biological function of the genes and polymorphisms. In addition, we will assess the interactions between these genetic variants and intermittent UV exposure history, i.e. sun exposure while wearing a bathing suit and indoor tanning device usage, on melanoma risk. This innovative work will move this field forward, by systematically evaluating these common variants using these complementary approaches. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohorts, including cohort characteristics, quality of design, high follow-up rate, large sample size, prospective host factor assessment, and high response rate of retrospective questionnaires. Our proposal will also take advantage of the previously identified and confirmed cases of melanoma as well as stored bio-specimens. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Project Narrative: Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma;however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. We propose to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies.